Abstract To reduce the prevalence of Alzheimer's disease (AD), scientists and policy makers have called for new models of the disease. The proposed project tests a novel model of how culture and genes may interact to influence AD and cognitive health. This project will provide the first investigation of whether a modifiable, culture-based environmental factor, negative age beliefs, exacerbates the effect of the genetic-risk-factor apolipoprotein E4 (APOE ?4) on adverse cognitive outcomes, including risk for AD, and whether positive age beliefs increase the likelihood that APOE ?2 leads to beneficial cognitive outcomes, including reduced AD risk. The proposed project builds on our findings with older individuals that (a) negative age beliefs can lead to greater stress, worse cognitive outcomes, and a greater accumulation of AD biomarkers; and (b) positive age beliefs can protect against these outcomes. This project also builds on the finding that APOE ?4 and ?2 account for less than half of aging-cognition variance; age beliefs may help to explain the remaining variance. Our proposed project with older persons will examine four specific aims for the first time: Aim 1. To examine whether the APOE genotype moderates age beliefs' impact on cognitive outcomes. We predict: (a) APOE ?4 carriers will show a greater detrimental impact of negative age beliefs on cognitive outcomes, compared to non-APOE ?4 carriers; and (b) APOE ?2 carriers will show a greater beneficial impact of positive age beliefs on cognitive outcomes, compared to non-APOE ?2 carriers. Aim 2. To examine whether our age belief-APOE genotype model helps to explain disparities by race and sex on cognitive outcomes. Considering that members of marginalized groups may be more sensitive to age stereotypes, we predict: (a) African Americans will show a stronger additive influence of APOE ?4 and negative age beliefs on detrimental cognitive outcomes, as well as a stronger additive influence of APOE ?2 and positive age beliefs on beneficial cognitive outcome, compared to Whites; and (b) women, compared to men, will show the same pattern as older African Americans described in Aim 2a. Aim 3. To examine whether psychosocial factors, related to age beliefs, influence Aim 1 patterns. We predict: (a) those higher in vulnerability factors (e.g., perceived discrimination) will show a stronger additive influence of APOE ?4 and negative age beliefs on detrimental cognitive outcomes, as well as a weaker additive influence of APOE ?2 and positive age beliefs on beneficial cognitive outcomes; and (b) those higher in resiliency factors (e.g., feeling useful to others) will show the reverse pattern. Aim 4. To examine whether psychological and behavioral mechanisms link the age belief-genotype predictor to cognitive outcomes. We predict: stress and physical activity will act as mediators of this association. This proposed project will draw on three longitudinal datasets with common key variables. This study meets the NIA priority to identify factors that could help explain disparities in AD risk by race and sex.